Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

Djuro Kosanovic, Himal Luitel, Bhola Kumar Dahal, Teodora Cornitescu, Wiebke Janssen, A H Jan Danser, Ingrid M Garrelds, Jo G. R. De Mey, Gregorio Fazzi, Paul Schiffers, Marc Iglarz, Walter Fischli, Hossein Ardeschir Ghofrani, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Irwin Reiss, Ralph Theo Schermuly

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Abstrakt

Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.

OriginalsprogEngelsk
BogserieEuropean Respiratory Journal. Supplement
Vol/bind46
Udgave nummer4
Sider (fra-til)1084-1094
ISSN0904-1850
DOI
StatusUdgivet - 2015

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